Non-Transgenic Cell Lines for Identifying Target Premalignant Genes
Berkeley Lab's S3 cell lines display partial loss of differentiation in 3DirBM Cultures.
Human breast epithelial cell lines were derived from a patient with fibrocystic breast disease. The epithelial tissue gave rise to non-tumorigenic S1 cells, from which more aggressive S2 cells were derived. Using colony size in three-dimensional laminin-rich basement membrane (3DlrBM) as an initial screening tool, the Bissell lab isolated three new cells lines, S3-A (mini), S3-B (midi), and S3-C (maxi) from the heterogeneous S2 cells. Comparing the S3 series to the parent S1 cells, as well as the malignant T4-2 cells (also derived from S2), showed that the "premalignant" S3s had an intermediate phenotype, as indicated by acini formation, polarization, and organization, as well as growth arrest after completion of morphogenesis. APPLICATIONS OF TECHNOLOGY:
Identifying target premalignant genes
Testing chemopreventive drugs and environmental pollutants
Establishing molecular determinants for identifying lesions likely to become malignant (avoiding over-treatment of some patients)
Detecting elevated PLK1 expression as a predictor of malignancy
Modeling premalignancy in humans
Non-transgenic, therefore not biased towards one or a few malignant pathways
Closely models transition to malignancy in vivo
Capable of reverting to premalignancy
After twenty years of research, Mina Bissell and her research team at Berkeley Lab have developed the first physiologically relevant and unbiased culture models of premalignant human breast cells. This premalignant cell line will enable researchers to identify and evaluate gene targets for breast cancer therapy in a culture system that more closely models the transition from premalignancy to malignancy in vivo than any other culture system to date. Using this model, researchers in the Bissell lab have already found that polo-like kinase (PLK1) plays a role in acquisition of invasiveness through basement membrane in culture and in vivo, suggesting a new function for this DNA damage response protein in extracellular matrix signaling.
The Berkeley Lab cells were derived from HMT-3522 human epithelial series (S2 cells) having a tumorigenic potential between non-tumorigenic and malignant cells. The cells exhibit a loss of differentiation in 3-D laminin-rich basement membrane, have the ability to invade through basement, but can acquire the potential to become invasive in the presence of conditioned medium from malignant cells. Because neither the process of immortalization nor the process of cell selection was induced by viral or oncogenic genes, the Berkeley Lab cell line model enables the study of different and unrelated pathways in the premalignant to malignant transition.
The Berkeley Lab cell lines provide a tool for establishing the utility of global gene expression analysis, protein expression profiling, and genome wide-determination of recurrent sequence aberrations in defining markers of high-risk premalignant lesions. Defining these markers and developing assays to detect them would prevent the over-treatment of patients with low-risk premalignant tumors. In addition, identifying several pathways to target in the complex network of extracellular signaling might enable the development of multiple therapeutics which could be switched if a patient developed side effects from a single therapy. The therapeutics might also be highly effective if given simultaneously.
The limits of this model are that the cells were derived from one patient and cannot be expected to reveal casual molecular factors for each type of breast cancer. Nevertheless, this system provides a well-characterized model of human breast cancer progression in culture.
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